Abstract: PUB180
Late-Onset COL4A4-Associated Nephropathy in a Heterozygous Hispanic Man with Preserved Kidney Function and Minimal Phenotypic Expression
Session Information
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Monogenic Kidney Diseases
Authors
- Rana, Bilal Azhar, New York City Health and Hospitals Jacobi, New York, New York, United States
- Vashisht, Archana, New York City Health and Hospitals Jacobi, New York, New York, United States
- Petras, Fnu, New York City Health and Hospitals Jacobi, New York, New York, United States
- Acharya, Anjali, New York City Health and Hospitals Jacobi, New York, New York, United States
Introduction
Alport syndrome is a genetically heterogeneous disorder caused by mutations in COL4A3, COL4A4, or COL4A5, presenting with hematuria, proteinuria, progressive renal dysfunction, sensorineural hearing loss, and ocular anomalies. While classic presentations occur in pediatric populations, heterozygous COL4A4 variants can lead to attenuated or late-onset disease. Recognition of atypical presentations in older adults remains a diagnostic challenge, particularly when clinical and histopathologic findings are nonspecific.
Case Description
A 66 year-old Hispanic male with history of well-controlled HIV (undetectable viral load, CD4 count 487), hypertension, coronary artery disease, and prior hemorrhagic stroke was referred for rising serum creatinine. Baseline creatinine was 1.4–1.6 mg/dL from 2019–2023, increasing to 1.7 mg/dL with UPCR 3,072 mg/g in July 2023. Urinalysis showed 42 RBCs in 2022. C3/C4 were normal. ANA, PLA2R, hepatitis serologies, and monoclonal studies were negative. Renal ultrasound (2021) revealed bilaterally echogenic kidneys with preserved cortical thickness and no hydronephrosis. Renal biopsy (August 2023) showed mild segmental GBM thinning without immune complex deposition. Pathology was interpreted as consistent with a type IV collagen disorder. Genetic testing revealed a heterozygous COL4A4 pathogenic variant, c.3022G>A (p.Gly1008Arg), confirming a molecular diagnosis of autosomal dominant (AD) Alport syndrome. No hearing loss (audiogram normal, 2019) or ocular involvement was documented. Family history was unknown. He was started on an ACE inhibitor in July 2023. By April 2025, creatinine was 1.5 mg/dL, eGFR 51 mL/min/1.73m2 (CKD 3A), and UPCR improved to 69 mg/g.
Discussion
This case highlights the diagnostic utility of genetic testing in evaluating CKD of unclear etiology, especially when clinical and histologic findings are subtle and clinical manifestations minimal. A heterozygous, pathogenic COL4A4 variant confirmed diagnosis of AD Alport syndrome in the absence of classic features. AD inheritance is seen in 20-30% of Alport cases. In older adults, collagen IV nephropathies are likely underrecognized due to nonspecific clinical and biopsy profiles. This case supports broader use of genetic testing in CKD and adds to the evolving spectrum of adult-onset COL4A-associated disease.